Dendritic cells (hereinafter abbreviated as “DCs”) are specialized antigen presenting cells that integrate a variety of incoming signals to orchestrate adaptive immune responses.
These cells have peculiar and opposite abilities, and therefore can be distinguished in two major and differently specialized subpopulations: on the one hand the effector proinflammatory DCs (also called proinflammatory DCs) and on the other hand the tolerogenic DCs (also called regulatory or DCreg).
The effector DCs, when activated, are crucial for the presentation of peptides and proteins to T and B lymphocytes and are widely recognized as professional antigen-presenting cells (APC), thanks to their ability to prime naïve T cells.
This subpopulation is involved in responses against infectious pathogens and tumors. Depending on the type of pathogen or antigen encountered and the profile of costimulatory molecules engaged, effector DCs have the capacity to induce different polarizations of T helper lymphocytes, that is to drive the development of Th1, Th2 or Th17 effector CD4+ T cells.
The effector DC subpopulation can be divided into at least three distinct cell subsets regarding the helper T cells they are able to prime: DC1 cell subset which drives the development of Th1 cells (cells producing type 1 cytokines IFN-γ and IL-2), DC2 cell subset which drives the development of Th2 cells (cells producing type 2 cytokines IL-4, IL-5 and IL-13), and DC17 cell subset which drives the development of Th17 cells (cells producing IL-17).
In contrast, tolerogenic DCs mediate the suppression of antigen (Ag)-specific immune responses via the induction of regulatory (also called suppressive) CD4+ T cells, T-cell anergy and clonal deletion of T-cells. Tolerogenic DCs are thus critically involved in promoting and maintaining clinical and/or immunological tolerance, as well as regulating excessive and undesired immune responses. Regulatory T cells exert immuno-suppressive functions which are crucial to contain autoimmunity, chronic inflammation, but also to promote allogenic stem cell engraftment and to mediate tolerance to solid tissue allografts (see the review article by Gregori. S, Tissue Antigens, 77: 89-99, 2011). Further, regulatory/tolerogenic DCs have been shown to suppress inflammatory response to inhaled allergens (Swiecki and Colonna, Eur. J. Immunol., 40:2094-2098, 2010; Kuipers, Vaccine, 23(37):4577-4588, 2005; Lambrecht, Allergy, 60(3): 271-282, 2005).
Therefore, bidirectional interactions between DCs and T cells initiate either effector or tolerogenic responses, which are crucial to establish appropriate defense mechanisms, while precluding uncontrolled inflammation and immune response.
However, since different Th-specific polarization are involved in immune responses against tumors, pathogens, allergens and in autoimmunity or graft rejection, inappropriate T helper lymphocyte polarization can be detrimental. For instance, failure of regulatory T cells function has been implicated in the development of many autoimmune diseases (Roncarolo et al., Nat. Rev. Immunol., 7:585-598, 2007). Further, when DCs initiate a tolerogenic response as opposed to an effector response in case of infectious diseases or tumors, regulatory T cells can contribute to immune escape of pathogens or tumor cells. Conversely, when DCs initiate an effector response rather than a tolerogenic response, autoimmune reactions, chronic inflammation or allergenic responses are observed.
Concerning the desensitization, a broadly accepted paradigm to explain the clinical efficacy of allergen-specific immunotherapy is a modulation of CD4+ T cell functions characterized by a shift from Th2 toward regulatory T cell responses. In this regard, the capacity of DCs to initiate and orient such effector or regulatory T cell responses suggests that those cells may contribute to both allergic inflammation and its resolution. For example, there is a growing body of evidence that DCs play a role in allergic sensitization through their capacity to induce and maintain allergen-specific Th2 responses (Lambrecht, Allergy, 60(3): 271-282, 2005). In contrast, tolerogenic DCs have been detected in the oral mucosa, and as such, appear to be essential in contributing to tolerance induction following sublingual immunotherapy.
Nowadays, there is a great interest in distinguishing these polarized DCs (i.e. effector DC subsets which drive the development of Th1, Th2 or Th17 effector CD4+ T, respectively termed DC1, DC2, DC17, and tolerogenic DC subsets which drive the development of suppressive/regulatory CD4+ T cells, induction of T-cell anergy and clonal deletion of T-cells) to assess the orientation of antigen-specific adaptive immune responses, and to monitor the efficacy of immunotherapy protocols.